Etude de la dynamique d'ions hydrophobes en solutions aqueuses par diffusion de neutrons et par simulation numérique

Symmetric tetraalkylammonium (TAA) cations are model systems to study the behaviour of hydrophobic ions. In this work, concentrated aqueous solutions of TAA bromides are investigated to obtain information on micro- scopic structure and dynamics of both the ions and solvent, by a combination of Neutron Scattering and Molecular Dynamics (MD) simulations. It is shown that TAA cations do not aggregate in aqueous solution even at high concentrations, they are penetrable for both the Br anions and solvent water molecules. The average water orientation is tangential around the cation surface, which contrasts with the simple alkali cations, such as Na+. Using quasi-elastic neutron scattering (Neutron Spin Echo and Time of Flight techniques) and with the aid of MD simulations, the dynamics in the coherent and incoherent neutron scattering signal is decoupled. The former is identified with the center-of-mass (CoM) motion of a single TAA cation, while the latter, based on the signal of individual H atoms of the TAA cation, is a complex combination of the CoM motion and H movements internal to the cation. MD helps to identify the timescale of the global cation rotation. The slowing down of water dynamics in these solutions relative to bulk water is also made evident, though the e ect is lower than might be expected.Les cations de tétraalkylammonium symétrique (TAA) sont des systèmes modèles pour étudier le comportement des ions hydrophobes. Dans ce travail, des solutions aqueuses concentrées de divers TAABr sont étudiées pour obtenir des informations sur la structure microscopique et la dynamique à la fois des ions et du solvant, par une combinaison de la diffusion des neutrons et de simulations par dynamique moléculaire (MD). Il est démontré que les TAA cations ne s’agrègent pas, même en concentration élevée et sont pénétrables à la fois par des anions et des molécules du solvant. L’orientation moyenne de l’eau de solvatation est tangentielle autour de la surface des cations, ce qui est différent de l'orientation observée avec les cations simples, comme Na+. L’utilisation conjointe des expériences de diffusion de neutron quasi-élastique (technique de l’Echo de Spin et de Temps-de-Vol) et de la simulation MD permet de séparer la dynamique contenue dans le signal cohérent et incohérent en diffusion de neutrons. Le premier est identifié avec le mouvement du centre-de-masse (CoM) du cation TAA, le deuxième, provenant des atomes individuels d’H du cation, est une combinaison complexe de ce mouvement de CoM et les mouvements des H à l’intérieur du cation. Le MD permet également d’identifier l’échelle caractéristique de la rotation globale du cation TAA. Le ralentissement des molécules de l’eau dans ces solutions est visible, mais moins important que prévu

Transferring a molecular foundation model for polymer property predictions

Transformer-based large language models have remarkable potential to accelerate design optimization for applications such as drug development and materials discovery. Self-supervised pretraining of transformer models requires large-scale datasets, which are often sparsely populated in topical areas such as polymer science. State-of-the-art approaches for polymers conduct data augmentation to generate additional samples but unavoidably incurs extra computational costs. In contrast, large-scale open-source datasets are available for small molecules and provide a potential solution to data scarcity through transfer learning. In this work, we show that using transformers pretrained on small molecules and fine-tuned on polymer properties achieve comparable accuracy to those trained on augmented polymer datasets for a series of benchmark prediction tasks

Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase

β-Lactam antibiotics are the most important and widely used antibacterial agents across the world. However, the widespread dissemination of β-lactamases among pathogenic bacteria limits the efficacy of β-lactam antibiotics. This has created a major public health crisis. The use of β-lactamase inhibitors has proven useful in restoring the activity of β-lactam antibiotics, yet, effective clinically approved inhibitors against class B metallo-β-lactamases are not available. L1, a class B3 enzyme expressed by Stenotrophomonas maltophilia, is a significant contributor to the β-lactam resistance displayed by this opportunistic pathogen. Structurally, L1 is a tetramer with two elongated loops, α3-β7 and β12-α5, present around the active site of each monomer. Residues in these two loops influence substrate/inhibitor binding. To study how the conformational changes of the elongated loops affect the active site in each monomer, enhanced sampling molecular dynamics simulations were performed, Markov State Models were built, and convolutional variational autoencoder-based deep learning was applied. The key identified residues (D150a, H151, P225, Y227, and R236) were mutated and the activity of the generated L1 variants was evaluated in cell-based experiments. The results demonstrate that there are extremely significant gating interactions between α3-β7 and β12-α5 loops. Taken together, the gating interactions with the conformational changes of the key residues play an important role in the structural remodeling of the active site. These observations offer insights into the potential for novel drug development exploiting these gating interactions

Dynamic Profiling of β-Coronavirus 3CL M^proProtease Ligand-Binding Sites

Data availability statement: The trajectories of Mpro simulations and models of the metastable states can be downloaded from 10.5281/zenodo.4782284.β-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. One such target is the main protease (Mpro) that plays an indispensable role in viral replication. The availability of over 270 Mpro X-ray structures in complex with inhibitors provides unique insights into ligand–protein interactions. Herein, we provide a comprehensive comparison of all nonredundant ligand-binding sites available for SARS-CoV2, SARS-CoV, and MERS-CoV Mpro. Extensive adaptive sampling has been used to investigate structural conservation of ligand-binding sites using Markov state models (MSMs) and compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-CoV homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor.There was no funding for this wor

Study of the dynamic of hydrophobic ions in aqueous solutions by neutron scattering and numerical simulation

Les halogénures de tétraalkylammonium symétrique (TAA) sont des systèmes modèles pour étudier le comportement des ions hydrophobes. Dans ce travail, des solutions aqueuses concentrées de divers TAABr sont étudiées pour obtenir des informations sur la structure microscopique et la dynamique à la fois du soluté et du solvant, par une combinaison de la diffusion des neutrons quasi-élastique (QENS) et de simulations par dynamique moléculaire (MD). Il est démontré que ces TAA cations sont pénétrables à la fois par des anions et des molécules de solvant et ne s'agrègent pas, même en concentration élevée (jusqu'à 3,56 m). L'orientation moyenne de l'eau de solvatation est tangentielle autour de la surface de cations ce qui est différent de l orientation observée avec des sels simples, comme NaBr. L utilisation conjointe des experiences de QENS (Neutrons Spin Echo et Temps de Vol) et de la simulation MD permet de séparer les contributions cohérentes et incohérentes. Les mouvements de translation et de rotation des solutés sont également étudiées en détail à différentes concentrations. Il est observé que la dynamique de solvant est relativement peu affectée dans le cas de solutions aqueuses d'halogénure de petits TAA comparée à celle dans les solutions contenant de plus grands TAA. Globalement, les comparaisons entre expériences de neutrons et simulations sont en bon accordPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF